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Fructose-Bisphosphate Aldolase a Is a Key Regulator of Hypoxic Adaptation in Colorectal Cancer Cells and Involved in Treatment Resistance and Poor Prognosis

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Fructose-Bisphosphate Aldolase a Is a Key Regulator of Hypoxic Adaptation in Colorectal Cancer Cells and Involved in Treatment Resistance and Poor Prognosis INTERNATIONAL JOURNAL OF ONCOLOGY 50: 525-534, 2017 Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis KENJI Kawai1, MAMORU UEMURA1,2, KOJI Munakata1,3, HIDEKAZU TAKAHASHI1, NAOTSUGU HARAGUCHI1, JUNICHI NISHIMURA1, TAISHI Hata1, CHU Matsuda1, MASAKAZU IKENAGA4, KOHEI Murata5, TSUNEKAZU MIZUSHIMA1,6, HIROFUMI Yamamoto1,7, YUICHIRO DOKI1 and Masaki MORI1 1Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871; 2Department of Surgery, National Hospital Organization Osaka National Hospital, Chuo-ku, Osaka, Osaka 540-0006, Japan; 3Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3100A Taubman Center, Ann Arbor, MI 48109-5368, USA; 4Department of Surgery, Higashi-osaka City General Hospital, Higashiosaka, Osaka 578-8588; 5Department of Surgery, Suita Municipal Hospital, Suita, Osaka 564-0082; Departments of 6Therapeutics for Inflammatory Bowel Diseases, and7 Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan Received October 21, 2016; Accepted November 23, 2016 DOI: 10.3892/ijo.2016.3814 Abstract. Hypoxia is an essential feature of cancer malignancy, the expression of fructose-bisphosphate aldolase A (ALDOA) but there are no methods for the routine detection of hypoxia- and its relationship with cancer metabolism. We found that inducible prognostic factors and potential therapeutic targets. ALDOA was induced by hypoxia in CRC-derived cell lines, We reported previously that the hypoxic tumor cells of meta- and univariate and multivariate analyses of microarray data static liver tissue from patients with colorectal cancer (CRC) from the resected CRC samples of 222 patients revealed that could be used as an ‘in vivo’ hypoxia culture model. Several ALDOA was an independent prognostic factor for CRC. We potential hypoxia-inducible genes were identified using this also analyzed the malignant potential of ALDOA in vitro model. Among them, one glycolytic enzyme was of special using overexpression and knockdown assays. We found that interest. There is currently increasing attention on glycolytic ALDOA was negatively related to chemosensitivity and radio- enzymes as potential therapeutic targets due to their associa- sensitivity and positively associated with proliferation, sphere tion with cancer-specific metabolism. To better understand the formation and invasion in both normoxia and hypoxia. These molecular mechanisms of cancer malignancy, we investigated associations were due to the roles of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle. These findings demonstrate that ALDOA is a hypoxia- inducible prognostic factor that is closely related to CRC Correspondence to: Dr Mamoru Uemura, Department of Surgery, malignancy, and also provide new insights into the importance National Hospital Organization Osaka National Hospital, 2-1-14, of ALDOA and glycolysis in cancer and suggest new targets Houenzaka, Chuo-ku, Osaka 540-0006, Japan for anticancer therapies. E-mail: [email protected] Introduction Abbreviations: ADM, adrenomedullin; ALDOA, fructose-bis- phosphate aldolase A; CA9, carbonic anhydrase IX; CRC, colorectal Colorectal cancer (CRC) is one of the most frequent cancers cancer; DFS, disease-free survival; EFNA1, ephrin-A1; EMT, in humans (1). Despite recent advances and new treatments, epithelial-mesenchymal transition; HIF1A, hypoxia-inducible factor 1-alpha; OS, overall survival; PCR, polymerase chain reaction; including combination therapy with anticancer and molecular PI, propidium iodide; PLOD2, procollagen-lysine, 2-oxoglutarate targeted drugs (2,3), CRC remains a major cause of cancer 5-dioxygenase 2; RIPA, radio immunoprecipitation assay; SCGB2A1, morbidity and mortality (4). Thus, there is still a need to iden- secretoglobin, family 2A, member 1; 5-FU, 5-fluorouracil tify new therapeutic targets in CRC. In the tumor microenvironment, cellular hyperplasia and Key words: fructose-bis phosphate aldolase A, chemoresistance, relative blood flow insufficiency often lead to tumor hypoxia. radioresistance, colorectal cancer, hypoxia To survive in this harsh environment, cancer cells develop adaptive responses to hypoxia that are mediated by the activa- tion of hypoxia-inducible genes. In this context, hypoxia is a major feature of cancer, and in hypoxic conditions, cancer cells 526 KAWAI et al: ALDOA IS A KEY REGULATOR IN THE HYPOXIC ADAPTATION OF COLORECTAL CANCER can develop into malignant cells that survive in the low-oxygen MCO-5MUV; Panasonic, Osaka, Japan) using a continuous environment. Previous reports have suggested associations infusion of a gas mixture (95% N2, 5% CO2). between hypoxia and solid tumors, including brain tumors (5), breast (6), liver (7), lung 8), ovarian (9), prostate (10) and Ethics statement regarding the use of clinical samples. The CRC (11). use of clinical samples was approved by the Human Ethics Microarray techniques allow researchers to detect Review Committee of the Graduate School of Medicine, hypoxia-induced genes. Most hypoxia-related experiments Osaka University. Written informed consent was obtained are based on in vitro conditions. However, the problem with from all patients included in the study. hypoxic models is that there are apparent differences between the experimental hypoxic models and actual in vivo hypoxic Clinical tissue samples. For western blot analysis, 6 surgical environments. In experimental hypoxic conditions, there are CRC samples from patients with no preoperative chemo- many unpreventable biases, such as the degree of hypoxia, the therapy or irradiation were randomly selected from samples duration of the hypoxic conditions, pH, growth factors and collected at Osaka University Hospital in 2016. For immuno- nutrients. Moreover, it is almost impossible to replicate the histochemical staining, 14 surgical samples of colorectal liver complex cellular interactions that occur in vivo in an in vitro metastases from patients with no preoperative chemotherapy environment. or irradiation were collected from 2012 to 2015 at the Osaka We reported previously that liver metastasis of CRC is University Hospital. like ‘in vivo’ hypoxia culture box, and that it is useful for identifying hypoxia-inducible potential prognostic factors Clinical sample collection and microarray analysis. and therapeutic targets (12). We used this model to identify Microarray analysis was performed as previously described the following novel hypoxia-inducible genes: Jumonji domain (12,16,24). A total of 222 clinical samples were collected from containing 1A (JMJD1A) (12), adrenomedullin (ADM) (13), consecutive patients who underwent curative (R0) resection ephrin-A1 (EFNA1) (14), procollagen-lysine, 2-oxoglutarate for CRC from 2003 to 2006 at the Osaka University Hospital 5-dioxygenase 2 (PLOD2) (15) and secretoglobin, family 2A, and its nine associated hospitals. The mean follow-up time member 1 (SCGB2A1) (16). was 40.2±26.4 months for patients with disease-free survival In the present study, we investigated the involvement of (DFS) and 52.7±18.5 months for all surviving patients (overall fructose-bisphosphate aldolase A (ALDOA) in CRC. ALDOA survival, OS). Table I shows the clinicopathological features of is one of the glycolytic enzymes that catalyzes the reversible the patients, including gender, tumor location, depth of inva- conversion of fructose-1,6-bisphosphate to glyceraldehyde- sion, lymph node metastasis, histological grade, Dukes' stage 3-phosphate and dihydroxyacetone phosphate (17). Notably, and vessel invasion. None of the patients whose samples were previous studies have reported that ALDOA is a downstream analyzed in this study received preoperative chemotherapy or target of hypoxia-inducible factor 1-alpha (HIF1A) (18,19), and irradiation. After surgery, patients with Dukes' stage C tumors several studies have reported a relationship between ALDOA were generally treated with 5-fluorouracil (5-FU)-based and cancers such as osteosarcoma (20,21), lung squamous cell chemotherapy. carcinoma (22) and hepatocellular carcinoma (23). The aim of the present study was to investigate the prog- Quantitative PCR. mRNA expression was determined by real- nostic value and the biological significance of ALDOA in time polymerase chain reaction (PCR). Total RNA was isolated CRC. We determined the expression of ALDOA in clinical using an RNeasy Maxi kit (Qiagen, Valencia, CA, USA), and samples and performed functional analyses of ALDOA using reverse transcription was performed using the reverse tran- overexpression and knockdown assays. Furthermore, our data scription system (Promega, Madison, WI, USA) according to suggest possible mechanisms that underlie the correlation of the manufacturer's instructions. The real-time PCR analysis ALDOA with cancer malignancy. was performed using the LightCycler 2.0 instrument system (Roche Diagnostics, Mannheim, Germany), based on Materials and methods Thunderbird SYBR qPCR Mix (Toyobo Co., Ltd., Osaka, Japan). The β-actin housekeeping gene was used as an internal Cell lines and culture conditions. Six human CRC cell lines control. The following primers were used in the present study: were used in this study. HCT116 and LoVo cells were purchased ALDOA: forward 5'-CTGCCAGTATGTGACCGAGA-3' and from the Japanese Collection of Research Bioresources Cell reverse 5'-ACAGGAAGGTGATCCCAGTG-3';
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